Genetic Basis of Abdominal Aortic Aneurysm

To identify the genetic (major genes) and environmental factors responsible for the significant aggregation of abdominal aortic aneurysm (AAA) among relatives of affected individuals.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta which can, if undetected, lead to rupture. The mortality associated with ruptured AAA is estimated to be 90 percent, while elective repair has a mortality risk of approximately 6 percent. Ruptured AAA is a leading cause of death among older Americans. The identification of markers of AAA risk could lead to preventive intervention. AAA aggregates in families, and segregation analysis shows that familial risk of AAA is best explained by the segregation of a major gene with an autosomal recessive mode of inheritance. DESIGN NARRATIVE: Affected relative pairs (primarily sibling pairs) with AAA and no evidence of a family history of a connective tissue disorder were genotyped for 150 highly informative microsatellite polymorphisms marking the autosomal genome at a resolution of 20 cM. The linkage between AAA and these loci was tested using robust affected pedigree member methods to identify genomic regions which might contain genes that predisposed individuals to develop AAA. The existence of predisposing gene(s) were confirmed and their location refined using a defined search strategy, genotyping at increasing levels of resolution, and re-analysis of family data. The predisposing gene(s) were identified by a combination of saturation mapping and molecular analysis of candidate loci. The association of AAA with environmental measures was investigated to determine an equation for estimating risk for relatives of AAA patients based upon environmental measures and genotype. Power calculations based upon the number and structure of families already collected demonstrated the feasibility of identifying genes that predisposed to AAA using this strategy, even in the presence of significant heterogeneity with respect to the loci involved. In addition to identifying genes that were necessary for AAA by linkage analysis, a series of analyses of association were undertaken to identify true susceptibility genes that were neither necessary nor sufficient to cause disease, but which modified an individual's risk of developing AAA. The study completion date listed in this record was obtained from the "End Date" entered in the Protocol Registration and Results System (PRS) record.

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St Jean PL, Zhang XC, Hart BK, Ferrell RE. Dinucleotide repeat polymorphism at the HPR locus. Hum Mol Genet. 1994 Nov;3(11):2081. No abstract available.

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Peters DG, Kassam AB, Feingold E, Heidrich-O'Hare E, Yonas H, Ferrell RE, Brufsky A. Molecular anatomy of an intracranial aneurysm: coordinated expression of genes involved in wound healing and tissue remodeling. Stroke. 2001 Apr;32(4):1036-42. doi: 10.1161/01.str.32.4.1036.

Peters DG, Zhang XC, Benos PV, Heidrich-O'Hare E, Ferrell RE. Genomic analysis of immediate/early response to shear stress in human coronary artery endothelial cells. Physiol Genomics. 2002 Dec 26;12(1):25-33. doi: 10.1152/physiolgenomics.00016.2002. Epub 2002 Dec 26.